Ligand-enabled Ni-catalysed enantioconvergent intermolecular Alkyl-Alkyl cross-coupling between distinct Alkyl halides

α-Tertiary aliphatic amides are key elements in organic molecules, which are abundantly present in natural products, pharmaceuticals, agrochemicals, and functional organic materials. Enantioconvergent alkyl-alkyl bond-forming process is one of the most straightforward and efficient, yet highly challenging ways to build such stereogenic carbon centers. Herein, we report an enantioselective alkyl-alkyl cross-coupling between two different alkyl electrophiles to access α-tertiary aliphatic amides. With a newly-developed chiral tridentate ligand, two distinct alkyl halides were successfully cross-coupled together to forge an alkyl-alkyl bond enantioselectively under reductive conditions. Mechanistic investigations reveal that one alkyl halides exclusively undergo oxidative addition with nickel versus in-situ formation of alkyl zinc reagents from the other alkyl halides, rendering formal reductive alkyl-alkyl cross-coupling from easily available alkyl electrophiles without preformation of organometallic reagents.

α-Tertiary aliphatic amides with a α-saturated stereogenic carbon center are key structural units in chemistry, functional materials and many related areas [1][2][3][4][5] . Thus, the development of versatile and straightforward methods to access saturated stereogenic centers in a highly enantioenriched manner has been attracting long-term interests from chemistry community 6 . Early efforts have been paid to the employing of chiral auxiliaries to control the desired stereochemistry, resulting in the use of stoichiometric amount of chiral auxiliaries as well as additional steps for their installation and removal from the target molecules 7 . Over the past decades, studies have been increasingly focused on catalytic approaches to access such stereogenic centers 8,9 , including Ni-catalysed enantioconvergent cross-coupling between an alkyl electrophile and an alkyl nucleophile (Fig. 1a) 10,11 . Over the past years, significant progress has been achieved in nickelcatalysed enantioselective cross-coupling of racemic secondary alkyl electrophiles with organometallic reagents [12][13][14][15][16][17][18][19][20] . This reaction mode has been well-developed and evolved into an inevitable tool for constructing saturated stereogenic carbon centers. Although the significant advances, this reaction mode requires stoichiometric, reactive, and often sensitive organometallic reagents, which usually require time-consuming preformation. To this end, one alternative is to use alkenes as masked alkyl nucleophiles in the presence of metal hydride to undergo enantioselective alkyl-alkyl cross-coupling [21][22][23][24] . Hydrometallation of alkenes through metal hydride insertion generates alkyl metallic intermediates in situ as alkyl nucleophiles. In 2019, Fu group reported a seminal work on Ni-H catalysed enantioselective alkyl-alkyl cross-couplings of 1-substituted alkenes as a surrogate of carbon nucleophile to couple with secondary alkyl bromides adjacent to amides and esters ( Fig. 1b) 25,26 . More recently, secondary alkyl bromides next to phosphates and ethers were successfully involved [27][28][29][30][31][32][33] . Accordingly, this strategy has evolved into an efficient cross-coupling of diverse alkenes with alkyl electrophiles to build saturated stereogenic carbon centers in the presence of metal hydrides 34,35 .
However, direct reductive cross-coupling between two distinct electrophiles is still one of the most straightforward, cost-effective, thus ideal alternatives to construct saturated stereogenic carbon centers [36][37][38] . Ni-catalysed cross-coupling reactions between organelectrophiles under reductive conditions have been extensively investigated for C sp2 -C sp3 bond formation [39][40][41][42][43][44] . To date, no example of non-enzyme-catalysed enantioselective C sp3 -C sp3 bond formation was reported 45 . Herein, we report a Ni-catalysed intermolecular crosscoupling between two different alkyl electrophiles under reductive conditions (Fig. 1c). The use of newly-developed chiral ligand enables construction of C sp3 -C sp3 bond by selective coupling of two distinct alkyl electrophiles, without the preformation of organometallic reagents.

Optimization of the reaction conditions
To prove the concept, we commenced the investigation using 1a and 2a as the prototype substrates using nickel catalysis to evaluate the reaction parameters. After extensive preliminary evaluation (See Supplementary Tables 1-5), we found the use of pyridine-BOX type ligands gave better results compared to other types of ligands in the presence of zinc (3.0 equiv) as sacrificing reductant, ferrous chloride (25 mol%), and cesium iodide (3.0 equiv) as additives. Among the tested known ligands, L1 gave the best result, delivering the desired cross-electrophile coupling product 3a in 67% yield with 70% ee ( Table 1, entry 1). Modifying the substituents at α-position to oxygen on the oxazolidine ring of iPr-PyBOX significantly altered the efficiency of the ligand for this reaction (  [7][8][9][10][11]. The use of ferrous chloride may facilitate the cross-coupling of 1a with 2a. In addition, the addition of 15-crown-5 may serve as an additive to enhance the solubility of inorganic salts in organic phase.
(S,S)-L20, the reaction of 1a with 1-iodopropane gave R-6 in 70% yield with 86% ee, while the reaction of 1b with ethyl bromide furnished the other isomer S-6 in 59% yield with 88% ee.

Mechanistic study
In order to gain insight into the mechanism of the reaction, we set up a series of reactions to shed light on the reaction pathways (Fig. 4). First, the reaction of 1a with 2a in the presence of a radical scavenger TEMPO under otherwise identical to standard conditions was conducted (Fig. 4a). The desired intermolecular cross-coupling product 3a was not formed. Instead, the adduct 7 of TEMPO with 1a was obtained in 85% yield, indicating α-bromoamides underwent a single electron transfer process in this transformation. Next, the reactions of alkyl bromides with preformed alkyl zinc reagents under the standard conditions were tested (Fig. 4b). When alkyl zinc reagent 8 was used instead of 1a to couple with 2a under standard conditions, no desired product 3a was detected, and only protonated product 8' was formed quantitatively, indicating alkyl zinc reagent 8 could not mediate the reaction under the standard reaction conditions. In contrast, the reaction of 1a with alkyl zinc reagent 9 under standard conditions delivered the desired cross-coupling product 3a in 87% yield with 89% ee. Further conducting the reaction with slow addition of alkyl zinc reagent 9 led to the formation of 3a in 83% yield with 94% ee, which is identical to the standard reaction conditions. These results suggest slow formation of alkyl zinc intermediate 9 in-situ to serve as intermediate for the reaction. To further prove the formation of alkyl zinc intermediates during the reaction, a real-time reaction course was conducted (Fig. 4c). The monitor the reaction process of 1a with 2a under standard conditions showed that no formation of 3a in the first 30 min, although the consumption of 2a was observed, indicating the induction time to form significant amount of alkyl intermediate to initiate the coupling reaction to generate 3a.
On the basis of experimental results and literature precedence [46][47][48] , a plausible mechanism is depicted in Fig. 5. First, Ni(II) was reduced by zinc to generate the ligated nickel (I) species (Int-A) in the presence of chiral ligand (L), which could undergo single electron transfer to 1 to give alkyl radical intermediate Int-B and Ni (II) intermediate Int-C. In the meantime, alkyl zinc reagent Int-D could be formed from 2 and zinc in the assistance with iodide, which could undergo transmetalation with Int-C to generate alkyl Ni(II) species Int-E. The rebound of intermediates Int-B and Int-E could form dialkyl Ni (III) intermediate Int-F, which would facilitate reductive elimination to furnish the final product 3 and regenerate Ni (I) species.

Discussion
In summary, an intermolecular enantioselective alkyl-alkyl crosscoupling between two alkyl electrophiles has been developed enabled by the efficient and selective cross-coupling reaction between two distinct alkyl halides under reductive conditions, representing an alternative for the construction of chiral C sp3 -C sp3 bonds. One alkyl halides in-situ formed alkyl nucleophiles with reducing metal to cross-couple with the other alkyl halides in a chemo-and enantioselective manner, circumventing the tedious and time-consuming preformation of alkyl metal species. We anticipate this will inspire enantioselective in-situ cross-coupling between alkyl electrophiles under reductive conditions to be evolved into one of the major strategies to build saturated carbon centers via enantioselective C sp3 -C sp3 bond-formation.  Table 1, entry 24. 15C5 = 15-crown-5. DME dimethoxyethane, DMA dimethylacetamide.

Data availability
The X-ray crystallographic coordinates for structures that support the findings of this study have been deposited at the Cambridge Crystallographic Data Center (CCDC) with the accession code CCDC 2089117 (4f) and CCDC 2239323 (7) (www.ccdc.cam.ac.uk/data_request/cif). The authors declare that all other data supporting the findings of this study are available within the article and Supplementary Information files, and also are available from the corresponding author upon request. Fig. 5 | Proposed mechanism for the reaction. A plausible reaction mechanism for the intermolecular alkyl-alkyl cross-coupling between distinct alkyl halides based on all experimental results and previous literature evidence.